ABSTRACT

Objective To determine the epidemiological features, course, and outcomes of patients
with SARS-related critical illness.

Design, Setting, and Patients Retrospective case series of 38 adult patients with SARS-related critical
illness admitted to 13 intensive care units (ICUs) in the Toronto area between
the onset of the outbreak and April 15, 2003. Data were collected daily during
the first 7 days in the ICUs, and patients were followed up for 28 days.

Main Outcome Measures The primary outcome was mortality at 28 days after ICU admission. Secondary
outcomes included rate of SARS-related critical illness, number of tertiary
care ICUs and staff placed under quarantine, and number of health care workers
(HCWs) contracting SARS secondary to ICU-acquired transmission.

Results Of 196 patients with SARS, 38 (19%) became critically ill, 7 (18%) of
whom were HCWs. The median (interquartile range [IQR]) age of the 38 patients
was 57.4 (39.0-69.6) years. The median (IQR) duration between initial symptoms
and admission to the ICU was 8 (5-10) days. Twenty-nine (76%) required mechanical
ventilation and 10 of these (34%) experienced barotrauma. Mortality at 28
days was 13 (34%) of 38 patients and for those requiring mechanical ventilation,
mortality was 13 (45%) of 29. Six patients (16%) remained mechanically ventilated
at 28 days. Two of these patients had died by 8 weeks' follow-up. Patients
who died were more often older, had preexisting diabetes mellitus, and on
admission to hospital were more likely to have bilateral radiographic infiltrates.
Transmission of SARS in 6 study ICUs led to closure of 73 medical-surgical
ICU beds. In 2 university ICUs, 164 HCWs were quarantined and 16 (10%) developed
SARS.

Figures in this Article

Severe acute respiratory syndrome (SARS) is a newly recognized illness
that has rapidly spread throughout Asia, North America, and Europe. As of
June 9, 2003, 8241 people in 30 countries have developed SARS leading to 784
deaths.1 The morbidity and mortality associated
with SARS has led to international concern.

The epidemiological findings and clinical presentation of SARS for the
initial cases in Canada and Hong Kong have been described.2- 5 SARS
produces an acute respiratory illness with 23% to 32% of patients becoming
critically ill.4,6 The burden
of illness, clinical features, and outcome may be different from acute lung
injury due to other etiologies. In addition, these outbreaks have caused a
significant strain on the health care system by the influx of patients and
the human resources issues related to quarantine and SARS infection in health
care workers (HCWs).

The objectives of this study were to characterize the epidemiology,
clinical characteristics, and 28-day outcomes of critically ill patients with
SARS, and to evaluate the impact of SARS transmission from critically ill
patients to HCWs. A better understanding of SARS-related critical illness
will allow for improved resource planning and better protection of HCWs and
may suggest effective interventions for the patients most seriously affected
by SARS.

METHODS

Study Design

We retrospectively studied consecutive critically ill adult patients
with suspected and probable SARS in the Toronto area who were admitted to
intensive care units (ICUs) between the onset of the Toronto outbreak and
April 15, 2003 (Figure 1). We included
13 hospitals (5 university, 8 community) known to care for SARS patients.
(A list of the participating hospitals appears at the end of this article.)
Identification of all critically ill SARS patients in these institutions was
achieved by collaboration with the Ontario Hospital Association and the City
of Toronto Department of Public Health (which were responsible for the mandatory
reporting of SARS), by communication among an ad hoc Toronto SARS Critical
Care group and by cross-reference with a database from a previous study that
reported the general characteristics of patients with SARS in 10 of our study
hospitals.5

Figure 1. Epidemic Curve of All Probable and
Suspected Cases of Severe Acute Respiratory Syndrome in Toronto by Source
of Infection, Demonstrating the Study Period

Suspected and probable SARS was defined according to the definitions
issued by the World Health Organization as of April 20, 2003.7 Suspected
SARS was defined by the presence of fever greater than 38°C, respiratory
symptoms, and a history of travel to a geographic location associated with
SARS transmission or close contact with a known SARS patient. Probable SARS
required the addition of lung infiltrates on chest radiograph. We defined
critically ill patients as those admitted to the ICU requiring mechanical
ventilation, inspired oxygen concentration on face mask greater than or equal
to 60%, or inotropic medication. To evaluate the proportion of patients with
suspect or probable SARS who became critically ill, we compared critically
ill patients with the total number of patients diagnosed with probable or
suspected SARS treated at any of the participating hospitals by April 15,
2003.

Data Collection

Data collection forms were created with input from a multidisciplinary
group of HCWs. Following approval from each hospital's research ethics boards,
experienced research assistants abstracted data retrospectively from the medical
records. Data were checked for errors by a second investigator through manual
and electronic inspection using prespecified range limits. The authors of
a recent report of SARS patients in Toronto provided a database of their general
characteristics during a similar period.5 This
database was used only to compare noncritically ill with critically ill SARS
patients. Twenty-nine (76%) of the patients discussed in this article were
part of this earlier study,5 which did not
address SARS-related critical illness. When occupational transmission of illness
was reported in any of the 5 university ICUs, we identified the number of
HCWs who were quarantined and who developed suspected or probable SARS. The
number of ICU bed closures resulting from SARS transmission or quarantine
was tracked in all ICUs.

Patient Characteristics

The following information was collected for each patient: age, sex,
occupation (HCW or non-HCW), time course of fever or respiratory symptoms,
contact or travel to a SARS-affected area, medical comorbidities, date of
hospital and ICU admission and discharge, date of initiation of and liberation
from mechanical ventilation, and the Acute Physiology and Chronic Health Evaluation
(APACHE) II and sepsis-related organ failure assessment (SOFA) scores.8,9

Acute respiratory distress syndrome (ARDS) was defined according to
established criteria.10 To evaluate whether
lung protective ventilatory support was provided, we identified patients who
received a threshold tidal volume greater than 8 mL/kg (actual body weight)
or had a peak airway pressure greater than 35 cm H2O on any 2 consecutive
days during the first 7 days in the ICU.11 We
used the threshold tidal volume of 8 mL/kg because we did not have measured
height and predicted body weight. When multiple daily measurements were performed,
those closest to 08:00 hours were recorded because this time corresponded
with the majority of daily measurements.

Follow-up and Outcome Measures

The primary outcome was mortality at 28 days after ICU admission. Secondary
outcomes included the proportion of SARS-related critical illness; patient
location and ventilation requirements at day 28; the number of tertiary care
medical-surgical ICUs placed under quarantine, and in those institutions,
the number of HCWs contracting SARS secondary to ICU SARS transmission. Intensive
care unit HCWs who became ill were followed up to determine their need for
critical care support.

Statistical Analysis

To determine association between variables and mortality, the Fisher
exact test was used for categorical variables and univariable logistic regression
was used for continuous variables. Variables considered included age; sex;
occupation; medical comorbidity (diabetes mellitus, ischemic cardiac disease,
chronic obstructive pulmonary disease); clinical features at admission (temperature,
heart rate, respiratory rate, presence of nonproductive cough, dyspnea, oxygen
saturation); admission laboratory values (lymphocyte count, lactate dehydrogenase
[LDH], calcium, creatine kinase); admission chest radiograph findings characterized
by unilateral, bilateral, or no disease; treatment with ribavirin, corticosteroids,
or antibiotics; tidal volume (per kilogram of actual body weight); and peak
pressure while receiving mechanical ventilation. When the clinical laboratory
data were sparse, exact logistic regression was used. The Kaplan-Meier method
was used to determine the probability of survival over the duration of follow-up
and to generate survival curves. All statistical tests were 2-tailed. Factors
were considered statistically significant at α less than .05. The SAS
System for Windows version 8.2 (SAS Institute Inc, Cary, NC) was used for
all analyses.

RESULTS

Characteristics of Study Patients

Of 196 patients with probable or suspected SARS in the 13 Toronto area
hospitals during the study period, 38 (19%) met inclusion criteria. Two additional
patients were admitted to ICUs for negative pressure isolation but did not
meet our definition for critical illness; hence, they were excluded.

Demographic characteristics of critically ill SARS patients are presented
in Table 1. Health care workers
comprised 18% of the critically ill patients. The median (interquartile range
[IQR]) age of all critically ill patients was 57.4 years (39.0-69.6 years)
compared with 45 years (34-57 years) reported for all patients with SARS.5 There was a predominance of older, non-HCWs (82%) in the critically
ill group with a median (IQR) age of 61 years (44-75 years) compared with
a preponderance of HCWs (58%) in the noncritically ill patients, who had a
lower median (IQR) age of 42 years (31-50 years).5 There
was a high rate of prior comorbidity, particularly diabetes, among patients
with SARS-related critical illness. The durations between initial symptoms
of SARS, hospital admission, ICU admission, and death are presented in Table 2.

Clinical Outcomes

Of the 38 patients admitted to the ICU, 31 (82%) met diagnostic criteria
for ARDS. Mechanical ventilation was required for 29 patients (76%), representing
15% of all SARS patients at study hospitals. The median (IQR) time from hospital
admission to institution of mechanical ventilation was 4.0 days (1.0-5.0).
Barotrauma occurred in 10 of these ventilated patients (34%). Other organ
dysfunction (defined as organ SOFA score >2) was less common—14 patients
(37%) developed cardiovascular dysfunction; 8 (21%), hepatic dysfunction;
and 4 (11%), renal dysfunction in the first 7 days in the ICU. Neuromuscular
blockade was used in 15 patients (representing 52% of ventilated patients),
high-frequency oscillatory ventilation in 3 patients (10%), nitric oxide in
8 patients (28%), and prone positioning in 1 patient (3%). Inotropic or vasoactive
medications were required by 14 patients (37% of ICU patients) and 2 patients
(5%) required hemodialysis.

Mortality, mechanical ventilation dependency, and patient location at
day 28 are presented in Table 3.
The median (IQR) ICU length of stay was 10.5 days (5-28 days). The 28-day
mortality rate for SARS patients admitted to the ICU was 34%, and was 45%
(13 of 29 patients) for those requiring mechanical ventilation. However, 6
patients (16%) remained on ventilatory support at 28 days. Late follow-up
at 8 weeks revealed that 15 patients had died for a mortality rate of 39%
(or 52% for those requiring mechanical ventilation), with 3 patients remaining
on ventilatory support.

Characteristics of Surviving vs Nonsurviving Critically Ill Patients

Table 4 compares characteristics
of surviving and nonsurviving critically ill patients with SARS with characteristics
of patients with SARS who did not require ICU admission.5 We
found that older age, a history of diabetes mellitus, admission tachycardia,
and elevated creatine kinase were associated with poor outcome. The presence
of bilateral radiographic lung infiltrates at admission was more common among
patients subsequently needing ICU care. Figure
2 presents the probability of survival over time for all critically
ill patients with SARS and for patients older than 65 years vs patients 65
years or younger. Only 3 of 10 patients (30%) older than 65 years were alive
at day 28 while 22 of 28 patients (79%) aged 65 years or younger were alive.

Impact on HCWs and Critical Care Resources

On 2 separate occasions, ICU patients transmitted SARS to HCWs in 2
of the 5 university medical-surgical ICUs in Toronto. The first episode occurred
when a patient with unsuspected SARS was treated for 30 hours in the absence
of respiratory precautions. When SARS was recognized, 69 HCWs were quarantined.
Seven HCWs subsequently developed SARS. All were hospitalized, but none became
critically ill. The second episode involved exposure during endotracheal intubation
of a hospitalized SARS patient. Although infection-control precautions with
N-95 respirator mask, gloves, and gowns were used, 9 HCWs developed SARS likely
related to a prolonged and difficult endotracheal intubation of a combative
patient. Eight of these HCWs were hospitalized, but none became critically
ill. This episode required 95 HCWs to be quarantined.

These 2 events led to 10-day closures of 35 critical care beds, representing
38% of the tertiary care university medical-surgical ICU beds in Toronto.
The loss of critical care capacity resulted in the cancellation of surgery
that would have required perioperative critical care monitoring, including
cardiovascular surgery and transplantation. In addition, there were 38 concurrent
bed closures due to ICU SARS transmission and quarantine of HCWs in 4 of 8
study community hospitals. This represented 33% of the Toronto community medical-surgical
ICU-bed capacity. Other events also affected critical care bed availability.
In 2 institutions, HCWs developed symptoms that were investigated for SARS
and subsequently found not to have met the World Health Organization definitions.
However, during the investigation period 1 ICU was closed for several days
and HCWs were quarantined.

COMMENT

In this study, we identified that a high proportion of patients with
probable and suspected SARS became critically ill. We found that the median
time from symptom onset to death was 19 days, with many deaths occurring beyond
the follow-up time of previously reported SARS epidemiological studies.2- 5 Although
recent media reports have suggested an apparently increasing SARS mortality,
we hypothesize that these results are due to longer follow-up studies like
ours, rather than a changing epidemiology of SARS. Our data confirm previous
observations that mortality is associated with older age,4 and,
that HCWs, who are often younger than other SARS patients, are less likely
to die.

We found that SARS-related critical illness predominantly involved a
single-organ system, respiratory failure. A much smaller proportion of patients
exhibited cardiovascular instability, and very few developed other organ failure
during the first 7 days of critical illness. Mortality at 8 weeks was 52%
among patients with SARS requiring mechanical ventilation. This mortality
rate is similar to the mortality rate of a large unselected series of patients
with ARDS requiring mechanical ventilation.12 High
tidal volumes administered to some patients with SARS may have contributed
to this mortality rate.13 We examined ventilation
for 7 days to reflect management during the initial phase of acute lung injury
due to SARS. The proportion of patients with SARS who developed barotrauma
in our study (34% of ventilated patients) is higher than reported for other
forms of acute lung injury or ARDS.13,14

We observed that diabetes mellitus was a common comorbidity among those
with SARS-related critical illness as was shown in the previous Toronto cohort,
which included many of our patients.5 The association
between tachycardia on admission and mortality likely reflects increased severity
of disease and is a common component of severity of illness scales.8 A high-serum LDH level on admission to the hospital
appeared to be associated with increased mortality among the critically ill
patients. However, the LDH level of noncritically ill and critically ill SARS
patients was not different. Lee et al4 have
demonstrated an association between peak LDH levels and mortality in SARS.
Increased serum LDH has previously been associated with several pulmonary
infections.15,16 Although this
finding is usually nonspecific, the observation that higher levels of LDH
may be associated with increased mortality in SARS is similar to the experience
with patients who have Pneumocystis carinii pneumonia.17,18

Critically ill patients with SARS are at high risk of infecting HCWs,
likely related to high-risk procedures predisposing to droplet spread and
to larger viral loads in these patients. Viral shedding appears to peak relatively
late in the course of the disease when patients become critically ill.6 For clinicians on the front lines caring for patients
with SARS, it is of concern that almost one fifth of critically ill patients
discussed in our study were HCWs. Although none have died, one continued to
require ventilatory support at 8 weeks. In a previous series of 138 patients
with a shorter follow-up period, a similarly good outcome in HCWs was noted.4 Whether the apparently better outcome in HCWs is an
age-related phenomenon, due to a lower viral inoculum or other as yet unexplained
factors, remains to be determined.

Early identification of patients likely to require critical care services
and the relatively slow progression to intubation that we observed should
allow for optimal management of these patients. Uncontrolled exposure to infecting
agents during invasive procedures such as intubation can be averted by the
early use of universal infection-control precautions and appropriate HCW training
and education. Early transfer to the ICU, avoidance of noninvasive ventilation,
and controlled endotracheal intubation with enhanced infection control precautions19 will hopefully minimize the occupational hazard.
During this outbreak, infection control precautions changed on an almost daily
basis as new evidence emerged. A number of HCWs were infected during intubations
while using precautions that were thought to be adequate at the time (N-95
respirator masks, gowns, gloves, goggles). This has led us to use more stringent
infection control precautions including powered air-purification respirators
for high-risk procedures.19,20 Increased
awareness of the risk of contact spread has led to the use of double gowns
and gloves. The risk of infection and concern about transmitting disease to
family resulted in significant stress among HCWs.21

Our study has a number of important limitations. The calculation of
the number of patients becoming critically ill may have been affected by transfers
to our study centers. However, since no other hospitals in the Toronto area
had significant numbers of SARS patients and interhospital transfer of SARS
patients was strongly discouraged during the study period, we believe that
our report is accurate. Our definition of critical illness required admission
to the ICU, and it is possible that a higher proportion of patients with SARS
were critically ill but cared for in hospital wards. Although this is a comprehensive
series of critically ill patients with SARS admitted to study ICUs, the sample
size is limited and we were unable to precisely identify all variables that
may influence outcomes such as specific therapies.

How is the critical illness and respiratory failure associated with
SARS different from severe respiratory failure due to other viral illnesses
such as influenza? The mortality rate for patients with SARS who require mechanical
ventilation may be similar to that observed during severe influenza outbreaks.22 However, a prominent difference is that SARS is much
more likely to progress from a mild to a severe disease in young, otherwise
healthy individuals—an uncommon feature of influenza infection.23 Furthermore, we identified the need for prolonged
mechanical ventilation and supportive critical care in critically ill patients
with SARS. This is important information for clinicians, health administrators,
and governments planning for ongoing and future outbreaks of SARS. In Toronto,
critical care resources were significantly strained during the SARS outbreak
as a result of the influx of SARS patients, the closing of several institutions
for quarantine, and illness or quarantine of HCWs. Affected health districts
in the future will need to increase their capacity to treat critically ill
patients in respiratory isolation. We highly recommend that all bedside clinicians
have the necessary equipment, protective devices, and most important, training
and experience to use such devices prior to the onset of a SARS outbreak.

Letters

The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with
the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.

This feature is provided as a courtesy. By using it you agree that that you are requesting the material solely for personal, non-commercial use, and that it is subject to the AMA's Terms of Use. The information provided in order to email this article will not be shared, sold, traded, exchanged, or rented. Please refer to The JAMA Network's Privacy Policy for additional information.

Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.

What is this ?

Article rental gives users the ability to access the full text of an article and its supplementary content for 24 hours.
Access to the PDF is only available via article purchase.